Visual Symptoms

Among the most common of such symptoms are the visual deficits, either qualitative and/or quantitative. Such symptoms are related to the suprasellar expansion of the pituitary tumor, with compression and distortion of the optic chiasm and consequent chiasmatic syndrome. That is characterized by visual field defect (classically, incomplete to complete bitemporal hemianopia) due to the compression of the nasal retinal fibers (Fig. 21-3). The deficit of one or of both the temporal hemi-fields begins in such a subdolous manner that it is not appraisable by the patient, in the superior temporal quadrants, progressing towards the bottom in a counterclockwise direction, for the left eye and in a clockwise sense for the right eye. Other perimetric defects are seldom present, such as binasal perimetric defects, resulting from a lateral compression of the chiasm; bilateral altitudinal hemianopia, from a lesion to the superior fibers or to the inferior ones, the latter being involved with greater frequency; homonymous hemianopia, because of the involvement of the posterior portion of the chiasm; and monocular perimetric defects.

FIGURE 21-3 Graphical representation of an automatic static perimetric exam in a patient with bitemporal hemianopia (right eye). A, Numerical map (in Db): in every retinic point examined the levels of the light threshold are shown. B, “Total deviation” chart that shows the difference between the threshold value recorded for the patient and the computerized value statistically normal per age. C, Representation by means of a scale of grays.

Besides the visual field deficits, loss of vision of various degrees, even to blindness, may be present. The visus, especially in the initial stages, when the tumor does not compress the fibers originating from the macula (which are situated in the posterior-median portion of the chiasm), may be preserved. The reduction of visual acuity is often unilateral or is not the same in both eyes. More rare is palsy of the eye musculature, palpebral ptosis, ophthalmoplegia, and diplopia due to the adenomatous mass growing laterally, compressing and/or invading the cavernous sinus and therefore the oculomotor nerves. Another impairment of the ocular motility that could be encountered is a dissociated vertical-pendular nistagmus (see-saw nystagmus), sometimes associated with bitemporal hemianopia, and thought to be related to a lesion of Cajal’s interstitial nucleus. A splitting of the images could also be present in the absence of any muscular palsy, and this symptom is due to the fact that for the patient with bitemporal hemianopia, vision is missing in the outer (temporal or lateral) half of both the right and left visual fields.

Headache

Another common symptom caused by endocrinologically silent pituitary tumors is headache, which does not seem to be correlated with the size of the adenoma.¹⁷ Such symptom is due to the stretching of the diaphragma sellae and/or the medial wall of the cavernous sinuses, caused by an even mild or moderate intrasellar hypertension.¹⁸

Endocrinologic Symptoms

Due to their usually large size, endocrinologically silent pituitary tumors can cause, indeed, endocrinologic symptoms. These are related with pituitary insufficiency caused by the compression on the residual gland and the stalk by the tumor mass and are most of the times subtle. As a matter of facts, patients harboring such tumors may present different symptoms of hormonal hyposecretion, such as secondary hypogonadism, oligo/amenorrhea in females (due to either hypogonadism and/or functional hyperprolactinemia), decreased libido, hypothyroidism, adrenal insufficiency, GH-insufficiency, etc. Such deficits can lead, ultimately, to complete pituitary insufficiency or panhypopituitarism.

Pretty common in case of macroadenomas is the functional hyperprolactinemia (AKA stalk effect) due to the compression/deviation of the pituitary stalk with consequent encroachment of the vessels of the pituitary portal system. This causes an insufficiency in the tuberoinfundibular pathway of the dopamine—an inhibitor of the prolactine production—with consequent disinhibition of the production of such hormone. Anyway, the increased serum levels of the HPRL are usually mild to moderate.

Diabetes insipidus is not a usual presenting symptom of nonfunctioning adenomas and, when present, should suggest reconsidering the diagnosis.

Cranial Nerve and Brain Symptoms

Although uncommon, deficits of one or more cranial nerves running inside the cavernous sinus may be present, depending on the grade of the involvement, in the event of compression of its medial wall or in the presence of a frank invasion of the sinus.

Exceptionally big tumors may cause psychiatric or other neurologic symptoms, such as personality changes and anosmia, due to the involvement of the frontal lobes, when the suprasellar expansion grows over the planum sphenoidale with shifting up the brain. Also, symptoms related with temporal lobe involvement, such as uncinate seizures, may be present, although rare.

Pituitary Apoplexy

Pituitary apoplexy is a relatively rare condition presenting with sudden headache, acute visual loss, ophthalmoplegia, altered level of consciousness, lethargy, and even collapse from acute adrenal insufficiency. It is caused by a hemorrhage into the tumor and/or its acute necrosis, with subsequent swelling and frequent spreading into the subarachnoid space, leading to other signs of meningeal irritation (Fig. 21-4). Clinical conditions or precipitating factors that are associated with an increased risk for such occurrence are coronary artery surgery and other major surgery, pregnancy, anticoagulant or antiaggregant therapy, and coagulopathies.¹⁹ The related acute and severe clinical syndrome demands glucocorticoid replacement and surgical decompression, usually trans-sphenoidal, if visual loss is severe and progressive. These patients typically require a full hormonal replacement therapy in the perioperative period. If the patient has a subclinical or a mild form of apoplexy and is clinically stable, it is prudent to measure the serum prolactin, since some patients with prolactinoma present in this fashion and may be successfully treated with medical therapy.

FIGURE 21-4 Preoperative coronal (A) and sagittal (B) contrast-enhanced sellar MRI showing a pituitary apoplexy. The mass compresses the optic apparatus, superiorly, and both the cavernous sinuses, laterally.

Pituitary Incidentalomas

The incidental discovery of a nonfunctioning pituitary adenoma is a fairly common occurrence. It usually happens when brain imaging studies are done for other reasons, such as motor vehicle accidents or head traumas. In such cases a more elaborate neuroradiologic work-up may be required, with the obtaining of a contrast-enhanced sellar MRI.

Neuroradiologic Evaluation

A correct neuroradiologic evaluation of a patient with a nonfunctioning pituitary mass is mandatory. The aim of the neuroradiologic study of a suspected pituitary mass is mainly based on the evaluation of the characteristics of the lesion (origin, structure, extension, and relationships) and the shape and location of the residual pituitary gland. Its purposes follow:

The gold standard among the radiologic studies available is the magnetic resonance imaging. A complete MR protocol should include, at least T1- and T2-weighted images and T1-weighted postcontrast (postgadolinium) images (Fig. 21-5) in the three orthogonal planes and 3-mm thick sections.²⁰ Complementary MR sequences are also useful, such as dynamic sequences; MR angiography, namely when one suspects the vascular nature of a lesion; diffusion-weighted and/or perfusion-weighted MRI; and MR spectroscopy (Fig. 21-6).

FIGURE 21-5 Preoperative sagittal (A) and coronal (B) and preoperative contrast-enhanced sagittal (C) and coronal (D) sellar MRI showing a large intra- and supra-sellar macroadenoma, strongly enhancing after contrast medium injection.

FIGURE 21-6 Preoperative axial MRI, diffusion-weighted sequence, of clinically nonfunctioning pituitary macroadenoma.

Fibrous adenomas are encountered in approximately 10% of cases²¹ and can be difficult to remove via the conventional trans-sphenoidal approach. In such cases, preoperative MRI may be useful in anticipating tumor consistency and allow planning of the surgical strategy correctly. Tumors with a hypo- or iso-intense appearance on T2-weighted MRI may be indicative of greater collagen content^21–23 and a more fibrous tumor consistency. In contrast, softer tumors are hyperintense on T2 (Fig. 21-7).

FIGURE 21-7 Preoperative coronal MRI, T2-weighted sequence, of a clinically nonfunctioning pituitary macroadenoma. The tumor mass is hyperintense with cystic areas within it, predicting a soft consistence of the tissue.

When a trans-sphenoidal approach is foreseen—especially the endonasal variant—axial and coronal CT scanning may be helpful in addition to an accurate assessment of the anatomy of the nasal cavities and the paranasal sinuses and for the definition of the best route from the nasal cavity toward the sella, since MR imaging alone does not provide the necessary detail of bone anatomy.²⁰ Axial and coronal CT scanning allows the neurosurgeon to more easily assess the three-dimensional (3D) aspects of the nasal and paranasal cavities, particularly the sphenoid bone, and the relationships with the sellar floor and carotid canals. CT study is essential in order to reveal the presence of eventual anatomic variations or pathologic changes of the cavities. Moreover, CT remains the diagnostic imaging study of choice in patients who are unable to undergo an MR study.

Although analysis of axial and coronal scans gives a detailed true depiction of rhino-sinusal anatomy, the 3D virtual endoscopy yields images similar to those provided by actual endoscopy, giving the surgeon a view before the operation and avoiding the complex task of mental reconstruction in the space of images obtained on traditional scan planes^20,24 (Fig. 21-8).

FIGURE 21-8 A, Three-dimensional surface CT reconstruction. B, Virtual endoscopy. Approach to the right nasal cavity. C, Virtual endoscopy. Entry into the right nasal cavity between the lateral wall and the septum. D, Virtual endoscopy. Identification of the middle turbinate. E, Virtual endoscopy. Entry into the sphenoid sinus with the intersinusal septum. F, Virtual endoscopy. Visualization of the sellar floor. NS, nasal septum; MT, middle turbinate; ∗, intrasphenoid septum; SF, sellar floor; PS, planum sphenoidale; C, clivus.

Ophthalmologic Evaluation

The ophthalmologist’s evaluation is of utmost importance when a suprasellar lesion is suspected, in all the stages of the disease from the diagnosis to the pre- and post-operative evaluation.²⁵ The visual field evaluation, by means of either the manual kinetic technique or the computerized threshold static perimetry (Fig. 21-3) and the study of visual evoked potentials (VEPs) are the most suitable exams to show eventual functional deficits due to chiasmatic involvement, as well as to monitor the preservation or vision recovery after surgery. VEPs are useful in the evaluation of the pharmacologic or surgical treatment, rather than for routine diagnostic purposes, where the basic test was and still remains the field exam. The examination of chromatic sensibility is not considered a routine investigation, but it should be performed in cases where the field evaluation and VEPs are normal, but there is still suspicion of chiasmatic compression based on neuroradiologic studies.

Endocrinologic Evaluation

The role of the endocrinologist in the preoperative settings of patients with endocrinologically silent pituitary tumors is of utmost importance. For such patients, a complete evaluation of the serum levels of the pituitary hormones together with the basal and functionality tests of the target organs of such tumors—including growth hormone, IGF-1, prolactin, TSH, T3, T4, FSH, LH, ACTH, and cortisol—is important to check for possible clinical or subclinical pituitary hypofunctions and to provide an adequate hormonal replacement therapy, if applicable. The correction of any eventual pituitary deficiency greatly helps improving the global outcome of these patients.

A full preoperative endocrinologic investigation is also conducted to ascertain the baseline pituitary gland function and to use its results to be compared with the postoperative ones, in order to demonstrate any postoperative pituitary function improvement or recovery or, conversely, any new hormonal deficit, also for medical legal purposes.

Medical Management

The medical approach to clinically silent pituitary adenomas has improved in recent years due to the availability of effective, well tolerated and safe molecules able to reduce, in some instances, the tumor mass.

It is now verified, by immunocytochemistry and ultrastructural studies, that the majority of such tumors are glycoprotein-producing, followed by nonfunctioning somatotroph, lactotroph, or corticotroph adenomas.¹⁶ As a matter of facts, a large proportion of nonfunctioning adenomas (up to 90%) is shown to secrete low amounts of either intact FSH and LH and/or their α- and β-subunits and the vast majority of nonfunctioning adenomas also express on cell membranes different subtypes of somatostatin and dopamine receptors (respectively, sst₁-sst₅ and D₁-D₅) in a variable amount. Based on this feature, both dopamine agonists and somatostatin analogues have a rationale in the treatment of such tumors and such fact has opened a new perspective of medical treatment for these lesions.

Somatostatin Receptors and Their Role

Somatostatin (growth hormone-inhibiting hormone [GHIH] or somatotropin release–inhibiting factor [SRIF]) is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein–coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. It is classified as an inhibitory hormone. Somatostatin analogs (SSAs) have been used in clinical practice over the past 20 years. They act through the somatostatin receptors, which have been demonstrated to be highly expressed in all pituitary adenomas with a predominance of sst₂ and sst₅ and infrequent expression of sst₄^16,26–28 Another analogue, the slow-release lanreotide (LAN), showing a similar receptor affinity for sst to that of OCT, was made available for intramuscular injections every 7 to 14 days. More recently, OCT and LAN have been made available for injections either intramuscular or subcutaneous every 28 to 56 days, respectively. The response to octreotide and lanreotide is predicted by the expression of sst₂^16,29 In nonfunctioning adenomas the receptor subtype expressed in a higher amount was found to be the sst₃ followed by the sst₂, also correlated with sst₅ expression.³⁰ The expression of sst₂ and sst₅ in nonfunctioning adenomas has been found to be associated with reduced cell viability by 20% to 80% (in 8 of 13 sst₂-positive tumors) and by 15% to 80% (in 10 of 13 tumors, all but three sst₅ positive).³¹ More recently, pasireotide (SOM230), a somatostatin analogue binding sst_1-3 and sst₅, completely abrogated the promoting effects of vascular endothelial growth factor (VEGF) on nonfunctioning adenoma cell viability.³²

Only few clinical trials have been conducted to evaluate potential effects of SSA in patients with nonfunctioning adenomas. However, a meta-analysis of such data revealed that tumor reduction was reported only in 12% of cases, while the vast majority of patients had stable remnant tumors.¹⁶ A still unexplained finding reported by some authors^33,34 is that OCT treatment was followed by a rapid improvement in headache and visual disturbances, without any change in tumor volume. This effect was likely not owing to a direct effect on tumor size but more likely to a direct effect on the retina and the optic nerve.³⁵ However, approximately in one third of the patients there was an improvement in visual field defects.¹⁶

Dopamine Receptors and Their Role

Dopamine receptors, namely the D₂ subtype, in the normal pituitary mediate the tonic inhibitory control of PRL secretion³⁶ by dopamine.³⁷ A meta-analysis of several studies¹⁶ has shown the presence of dopamine binding sites (most likely D₂) in nonfunctioning adenomas. Furthermore, in gonadotropin-immunopositive adenomas, the D₂ were mainly localized in LH- and FSH-immunopositive cells.³⁸ Anyway, the D₂ receptor is not the only dopamine receptor expressed in the pituitary gland. Indeed, the D₄ receptor, in particular its D_4.4 variant, is also expressed, although its role in the physiology of the pituitary gland is not known.³⁹ Cabergoline is the actual most commonly used dopamine agonist, able to inhibit in vitro the α-subunit concentration in 56% of cases and such result was associated with D₂ expression,⁴⁰ while the tumor shrinkage after DA therapy is 27.6%.¹⁶

A recent study of our group⁴⁰ demonstrated that 1-year treatment with cabergoline at the dose of 3 mg/wk induced a more than 25% tumor shrinkage in 56% of patients with histologically proven nonfunctioning adenomas and such shrinkage was significantly correlated with the expression of the D₂ isoform. The counterpart of such evidence was the finding of tumor regrowth after stopping the dopamine-agonist treatment,⁴¹ thus supporting the use of such treatment in these subjects.

Cumulative Role of Somatostatin and Dopamine Receptors

It is known that D₂ and sst₅ physically interact through hetero-oligomerization to create novel receptor with enhanced functional activity.^16,42